Abeta has emerged as a key molecule in the pathogenesis of Alzheimer's Disease (AD). This proposal will exploit the dependence of Abeta formation on the availability of the beta-site amyloid cleaving enzyme (BACE1) in order to reduce or block production of Abeta. Transgenic mice that express mutated human amyloid precursor protein (APP) show dramatic elevations in Abeta that parallel those seen in sporadic AD cases. Additionally, these mice show learning deficits and alterations in neuronal biophysical properties that underlie learning. This proposal will test the hypothesis that the removal of BACE1 from the genome will rescue the learning abilities and altered biophysical properties from the overexpression of Abeta in the "Westaway" mouse. Eyeblink conditioning, one of the most well characterized neuro-behavioral systems for learning and memory, and alterations in the amplitude of the afterhyperpolarization (AHP) and spike frequency accommodation (Accom) will respectively be used as behavioral and biophysical assays. The progeny of the Westaway and BACE knockout mice will comprise the four geneotypes that are required to test this hypothesis: The results should indicate whether or not a beta-secretase inhibitor will be a viable therapeutic agent for the treatment of AD.